CLINICAL PRACTICE

National Consensus on Portal Hypertension Management

in Indonesia

Juferdy Kurniawan1*, Andri S. Sulaiman1, Cosmas Rinaldi A. Lesmana1,

Putut Bayupurnama2, Muhammad Begawan Bestari3, Fardah Akil4,
Rino A. Gani1, Irsan Hasan1
1
Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto
Mangunkusumo Hospital, Jakarta, Indonesia.
2
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine Universitas
Gadjah Mada - Dr. Sardjito General Hospital, Yogyakarta, Indonesia
3
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine Universitas
Padjajaran - Dr. Hasan Sadikin Hospital, Bandung, Indonesia
4
Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine Universitas
Hasanuddin - Hasanuddin University General Hospital, Makassar, Indonesia.

* Corresponding Author:
Juferdy Kurniawan, MD. Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine Universitas
Indonesia - Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71, Jakarta 10430, Indonesia. Email: juferdy.k@
gmail.com

ABSTRACT
Portal hypertension is a clinical syndrome that consists of hypersplenism, ascites, gastroesophageal varices,
and encephalopathy. This condition is marked by increased portal pressure gradient and may occur with or
without liver cirrhosis. To date, portal hypertension remains as the leading cause of severe complications and
death of a patient with chronic liver disease, especially liver cirrhosis. Therefore, thorough understanding about
management of portal hypertension is strongly required, especially considering that many complications of
portal hypertension require early diagnosis and treatment to improve the prognosis of the patients. Additionally,
although hepatic venous pressure gradient (HVPG) measurement has become a gold standard procedure for
measuring portal pressure in the last twenty years, utilization of this method in Indonesia has been hindered by
reluctance of the patients due to its invasiveness, high cost, and limited availability. This consensus is developed
with evidence-based medicine principles to provide a guideline for portal hypertension management for general
practitioners, specialists, and consultants, to achieve better clinical outcomes of portal hypertension in Indonesia.

Keywords: portal hypertension, liver cirrhosis, chronic liver disease

INTRODUCTION cirrhosis, structural changes in liver sinusoids,

Portal hypertension is a clinical syndrome
that consists of hypersplenism, ascites,
gastroesophageal varices, and encephalopathy.
This condition is marked by increased portal
pressure gradient in different levels of the
portal vein system. Portal hypertension can
occur with or without liver cirrhosis. In liver
such as liver fibrosis and production of
regenerative nodules, can increase intrahepatic
resistance; thus, increasing the portal pressure.
Increased production of nitric oxide (NO)
in splanchnic circulation can also induce
splanchnic vasodilatation. Eventually, splanchnic
vasodilatation will increase portal blood flow,

324 Acta Med Indones - Indones J Intern Med • Vol 54 • Number 2 • April 2022
Vol 54 • Number 2 • April 2022 National Consensus on Portal Hypertension Management in Indonesia

causing worsened portal hypertension. As a
result, there will be abnormal circulation in the
form of hyperdynamic circulation, leading to
other complications.1,2
To date, portal hypertension remains as the
leading cause of severe complications and death
in a patient with liver cirrhosis. Additionally,
although in the last twenty years hepatic venous
pressure gradient (HVPG) measurement has
become a gold standard procedure for measuring
portal pressure, utilization of this method has
been hindered by its invasiveness and limited
availability, especially in less specialized medical
centers. Therefore, this consensus is developed
to provide a guideline for portal hypertension
management for general practitioners, specialists,
and consultants, to achieve better clinical
outcomes of portal hypertension in Indonesia.
EPIDEMIOLOGY
Chronic liver disease has affected
approximately 300 million people around the
world. Globally, the incidence and prevalence
of liver cirrhosis are still increasing every year.
In Indonesia, ten healthcare centers reported
that more than 1,500 patients were diagnosed
with liver cirrhosis in 2020. Unfortunately,
gastrointestinal endoscopic examination was
performed only in a small portion of the patients
(35.5% patients with liver cirrhosis) (Figure 1).3
Liver cirrhosis is also the fourth most common
cause of death due to non-communicable
diseases. The death rate caused by liver cirrhosis
has increased up to 65% in the last 17 years.4
A cumulative data in Cipto Mangunkusumo
National General Hospital showed that patients
with liver cirrhosis are dominated by male gender
(77%) and Child-Pugh A category (51%). Other
reports demonstrated an increase in death caused
by liver cirrhosis and hepatocellular carcinoma,
which is estimated to be 50 million deaths
annually in the last two decades.3,5
CLASSIFICATION
As mentioned above, HVPG measurement
is currently the gold standard to evaluate portal
pressure, as well as the best indirect method to
assess portal vein pressure. HVPG is defined as
the pressure gradient between portal vein and
inferior vena cava. The normal range of HVPG is
3-5 mmHg. Diagnosis of portal hypertension can
be determined if HVPG is higher than 5 mmHg.1,2
Mild Portal Hypertension
In general, patients with compensated liver
cirrhosis usually do not show any symptoms.

Prevalence of Esophageal Varices in Patients with Liver

Cirrhosis Which Were Found by Gastrointestinal Endoscopic
Examination
120,00%
100,00%
80,00%
60,00%
40,00%
20,00%
0,00%
Wahidin Cipto
Adam Moeward Hasan Abdoel Syaiful
Sudirohu Soetomo Mangunk Kandao Sanglah
Malik i Sadikin Moeloek Anwar
sodo Hospital usumo Hospital Hospital
Hospital Hospital Hospital Hospital Hospital
Hospital Surabaya Hospital Manado Denpasar
Medan Surakarta Bandung Lampung Malang
Makassar Jakarta
Prevalence 91,25% 100% 96,50% 72,30% 92,50% 71,10% 97,10% 84,50% 81,00% 72,00%

Prevalence

Figure 1. Prevalence of esophageal varices (%) in patients with liver cirrhosis diagnosed with gastrointestinal
endoscopic examination in Indonesia (2020).

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Compensated liver cirrhosis itself can be in patients with or without complications is to

differentiated into mild portal hypertension
and clinically significant portal hypertension
(CSPH).1,6 Mild portal hypertension is diagnosed
when HVPG is within the range of 6-9 mmHg. The
therapeutic goal is to prevent the progressivity
into CSPH.6,7
Clinically Significant Portal Hypertension
(CSPH)
CSPH is diagnosed when HVPG is ≥ 10
mmHg. Increase of portal pressure by more than
10 mmHg will contribute to the progression
of liver cirrhosis into more advanced stages.
Patients with CSPH can be present with or
without complications. The therapeutic goal
prevent any decompensation events, especially
gastroesophageal variceal bleeding.6,7
Clinical Stages of Portal Hypertension
Clinical stages and manifestation of
portal hypertension depend on the presence
of decompensation, as well as the presence of
esophageal varices and other complications of
portal hypertension in liver cirrhotic condition.
Therefore, the therapeutic goal needs to be
adjusted with the clinical stages (Table 1).6,7
A study conducted by Procopet, et al. 8 also
highlighted the association between HVPG
measurement and clinical outcomes in patients
with portal hypertension (Table 2).

Table 1. Stages, clinical manifestation, and therapeutic goal of portal hypertension in patients with compensated and
decompensated liver cirrhosis.6,7
Stages Compensated Liver Cirrhosis Decompensated Liver Cirrhosis
HVPG
< 10 > 10 > 12
(mmHg)
Varices
No No Yes Yes

Portal Acute History of History of

Hypertension variceal variceal bleeding variceal bleeding
No No No
Complications bleeding without other with other
complications complications
Therapeutic Prevent Prevent the Prevent the Bleeding Prevent the Prevent the
Goal the decompensated decompensated control, progressivity of progressivity of
CSPH condition condition (the early decompensated decompensated
first episode of prevention condition (the condition and
bleeding) of bleeding continuous mortality or other
recurrence bleeding) complications
and and other
mortality complications

Table 2. Association between portal pressure measurement and clinical outcomes in patients with portal hypertension.8
HPVG (mmHg) Clinical Outcomes
<5 Normal
6-9 Mild portal hypertension
>6 Progressivity of chronic viral hepatitis, high risk of recurrence after liver transplantation
10 Clinically significant portal hypertension (CSPH)
>10 Progression into esophageal varices, ascites, decompensation, advanced hepatocyte
abnormalities, decompensation after liver resection
>12 Esophageal varices bleeding
>16 High mortality
> 20 Failure to bleeding control
> 22 High mortality in severe alcoholic hepatitis

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PATHOGENESIS
As time goes by, production and accumulation
of extracellular fibrosis in the liver, which were
caused by chronic liver injury, can also induce
septal fibrosis progressively. Consequently,
septal fibrosis will inhibit oxygenation and blood
diffusion in the liver parenchyma. The final stage
of liver destruction is marked by the significant
distortion of the anatomical structure of the
liver, such as diminished normal hepatocytes,
microvascular and macrovascular changes,
neovascularization, formation of nodules, and
portosystemic shunt.1 Another main characteristic
of chronic liver disease is a long asymptomatic
period. In the first phase (compensated cirrhosis),
the patient may show no sign or only minimal
symptoms. In that period, portal hypertension
occurs minimally in line with decreased liver
function. Portal hypertension is a critical process
of the transition from compensated cirrhosis into
the decompensated state, which is also marked
by clinical complications, such as ascites,
acute variceal bleeding, spontaneous bacterial
peritonitis (SBP), hepatorenal syndrome (HRS),
and hepatic encephalopathy.3,5
Figure 2. Pathophysiology of portal hypertension (Adapted from [10]).
Portal pressure is mainly influenced by
vascular resistance and portal venous system
blood flow (Figure 2).9 Increased portal pressure
is caused by increased intrahepatic resistance and
portal blood flow.10 The increase of intrahepatic
resistance is caused by mechanical (structural
distortion of liver parenchyma) and functional
(an increase of intrahepatic vascular tone caused
by the reduced vasodilatation and imbalance
between vasoconstrictor and vasodilator) factors.
There are two different mechanisms associated
with NO production which may cause increased
portal blood flow. The increase of NO production
will induce splanchnic vasodilatation, leading to
increased portal blood flow. Higher concentration
of NO can also induce vasodilatation in systemic
circulation, causing arteriole hypotension and
relative renal hypoperfusion. Both conditions can
stimulate the activation of the renin-angiotensin-
aldosterone system (RAAS), promote fluid and
sodium retention, cause blood augmentation,
and increase cardiac output. As a result, blood
flow into the portal system will be increased, and
portal pressure will also increase.11
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Increased portal pressure will signal the
splanchnic system to induce vasodilatation,
and thus, leading to increased blood flow
into the portal system. A factor associated
with this condition is production of local
vasoactive substances by vascular endothelium
(NO, prostacyclin, carbon monoxide). The
angiogenesis mechanism is stimulated by
vascular endothelial growth factors (VEGF)
and platelet-derived growth factors (PDGF).
NO also plays an important role to induce the
splanchnic vasodilatation and angiogenesis
process. The concentration of NO in hepatic
circulation will be decreased, but it will be
increased in the splanchnic area.10,11
Portal hypertension also stimulates
the production of portosystemic collateral
vascular as a response to the increase of
portal pressure. Changes of portal pressure is
detected by intestinal microvascular cushion
and artery from splanchnic circulation. The
microvascular cushion will then produce
several angiogenic factors, such as VEGF
and placental growth factors (PlGF), which
will stimulate the formation of portosystemic
collateral vessels. The formation of collateral
vessel or angiogenesis is an important process
to form esophageal varices and ascites.10,12
Portal hypertension also induces hyperdynamic
circulation through the ꞵ-adrenergic system as a
response towards systemic hypotension.10 This
condition is marked by reduced mean arterial
pressure (MAP), reduced systemic vascular
resistance (SVR), and elevated cardiac index
(CI).12,13
DIAGNOSIS
There are several methods to measure
portal vein pressure, and currently, hepatic
vein catheterization is considered as the best
method. The difference between wedged
hepatic venous pressure (WHVP) and free
hepatic venous pressure (FHVP) is called
HVPG. Therefore, HVPG describes a pressure
gradient between portal vein and inferior vena
cava.6,7,14 A study reported that HVPG > 10
mmHg is an independent indicator for varices,14
decompensation (variceal bleeding, ascites,
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Acta Med Indones-Indones J Intern Med
encephalopathy),15 increased hepatocellular
carcinoma incidences (up to 6-folds increase),
and worsened conditions after liver resection.16
In compensated CSPH, the value of HVPG >
16 mmHg is a prognostic factor for clinical
decompensation.17 In acute variceal bleeding,
the value of HVPG > 20 mmHg is also a
prognostic factor of recurrent bleeding,
therapeutic failure, and higher mortality.18
Non-Invasive Examination
Clinical Examination
Clinical examination of portal hypertension
consists of physical examination, laboratory
examination, imaging studies, liver stiffness
measurement, and spleen stiffness measurement.
Spider nevi or abdominal portosystemic
collateral signs can be found in patients
with portal hypertension through physical
examination. Other common clinical findings
are splenomegaly and ascites.6
Biomarker Examination
One of the most common laboratory findings
in portal hypertension is thrombocytopenia.
Thrombocytopenia is associated with HVPG
and gastroesophageal varices, but it is not
accurate in diagnosing and excluding portal
hypertension or gastroesophageal varices.18
Several biomarkers have been evaluated for
diagnosing CSPH or severe portal hypertension
(Table 3). However, most studies were
conducted with small sample size, with history
of alcohol consumption as the most common
etiology of chronic liver disease. In addition, not
all serum biomarker examinations are available
widely. In conclusion, further validation studies
are still needed before these biomarkers can be
applied in daily clinical practices.
Other examinations to measure portal
hypertension with non-invasive methods are
AST to Platelet Ratio Index (APRI) score and
Fibrosis-4 (FIB-4) index. APRI can be used as
a value or index of reference to predict severe
esophageal varices. The measurement of APRI
and FIB-4 are recommended by World Health
Organization (WHO) to assess the degree of
liver fibrosis.27
Vol 54 • Number 2 • April 2022 National Consensus on Portal Hypertension Management in Indonesia

Table 3. Summary of studies which evaluated serum biomarkers for portal hypertension examination in liver cirrhotic patients.
No. Authors Biomarkers Etiology Results
1. Busk, et al. Tissue inhibitor n = 84 (dominantly TIMP-1 is significantly correlated with HVPG
(2014)19 metalloproteinase caused by alcohol (r = 0.40; p < 0,0001)
-1 (TIMP-1) consumption) For HVPG ≥ 12 mmHg
Threshold value: 173.9 ng/mL with sensitivity
99%, specificity 49%, NPV 86%, PPV 88%
Cut-off: 33.6 ng/mL, sensitivity 57%,
specificity 93%, NPV 33%, PPV 98%
2. Sandahl, et al. CD163-fibrosis Estimation cohort = 80 For CSPH detection (HVPG > 10 mmHg):
(2015)20 portal hypertension
score
-0.05xsCD163 Alcohol = 31 Cohort estimation
(mg/L) + Viral = 41 Threshold value: 1.4; sensitivity 100%,
0.03xP3NP (mg/L) specificity 25%, PPV 93%, NPV 100%
+ 0.021x HA (mg/L) Others = 8 Threshold value: 3.6; sensitivity 70%,
+ 0.001xTIMP-1 specificity 88%, PPV 99%, NPV 27%
(mg/L)
Validation Cohort = 80 Validation cohort
Alcohol = 63 Threshold value: 1.4; sensitivity 98%,
specificity 50%, PPV 89%, NPV 94%
Others = 14 Threshold value: 3.5; sensitivity 92%,
specificity 69%, PPV 93%, NPV 73%
3. Leeming, et al. Type IV Collagen n = 94 Correlation coefficient between Pro-C5 and
(2015)21 (Pro C5) HVPG: r = 0.33, p < 0.01
Alcohol consumption For CSPH Detection:
Threshold value: 330 ng/mL; sensitivity
79.7%, specificity 64%, PLR+: 2.2; NLR:
0.32; AUC: 0.73
For detection of HVPG > 16 mmHg vs 10-16
mmHg:
Threshold value: 346 ng/mL; sensitivity
80.5%; specificity 48.3%; PLR 1.6; NLR 0.4;
AUC: 0.68
4. Hametner, et al VITRO Score n=236 For CSPH detection:
(2016)22 (Von Willebrand Alcoholism = 93 Threshold value > 1.58; AUC: 0.86 (95% CI
Factor Antigen/ Hepatitis C = 67 0.81-0.91); sensitivity 80%, specificity 70%,
Thrombocyte Ratio) PPV 93.2%, NPV 40.1%
NASH = 29
Others = 19
Unknown = 28
5. Bruha, et al. Osteopontin n =154 Correlation between osteopontin and HVPG,
(2016)23 p = 0.002, r = 0.25
Alcoholism = 112 For detection of HVPG > 10 mmHg:
Viral = 112 Threshold value: 80 ng/mL; sensitivity 75%,
specificity 63%, PPV 92%, NPV 31%; AUC
0.763
Others included NASH For detection HVPG > 12 mmHg:
= 20
Threshold value 90 ng/mL; sensitivity 71%,
specificity 62%, AUC 0.725
6. Lim, et al. Serum Apelin n = 215 Association between s-apelin and HVPG (R2
(2016)24 = 0.356, p < 0.001)
Alcoholism = 155 AUC for prediction of CSPH: 0.962
HBV = 36 Mean of s-apelin concentration in CSPH
vs non-CSPH: 946.3±155.0 pg/mL vs
550.9±126.6 pg/mL, p < 0.001
HCV = 3
Alcoholism and HBV
infection = 12
Alcoholism and HCV
infection = 2
Cryptogenic = 7

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7. Kirnake, et al. APRI n= 277 Correlation between APRI and HVPG

(2018)25 (Spearman’s rho = 0.450, p < 0.001)
Alcoholism=135 For detecting HVPG > 12 mmHg.

Cryptogenic/NASH Threshold value: 0.876; sensitivity 71%

= 104 (95% CI 65-77%), specificity 78% (95% CI
65-89%), PPV 94% (95% CI 90-96%), NPV
38% (95% CI 32-44%), AUC 73% (95% CI
67-78%)
Hepatitis B = 8
Hepatitis C = 23
Hepatitis B and C = 3
8. Zou, et al. von Willebrand Meta-analysis from six
(2019)26 Factor (vWF) studies (n=994)
Alcohol (282), viral For HVPG > 10 mmHg: pooled sensitivity
(260), others etiologic 82% (95% CI 78-86%); specificity 76% (95%
(N/A) CI 68-83%); PLR: 3.11 (95% CI 1.99-4.86);
NLR: 0.21 (95% CI 2.49-4.72); NLR: 0.21
(95% CI 0.11-0.40); AUC: 0.87 (95% CI 0.80-
0.94)
For HVPG > 12 mmHg: pooled sensitivity
86% (95% CI 80-90%); specificity 75% (95%
CI 66-83%); PLR: 3.43 (95% CI 2.49-4.72);
NLR: 0.19 (95% CI 0.14-0.27)

Equation (1):
AST (upper limit normal)
APRI = x 100 x 10� L
Thrombocyte Count
Equation (2):
Age (Year)
FIB − 4 = x AST
Thrombocyte Count x √𝐴𝐿𝑇
A study by Kirnake V, et al. on 277 patients
with liver cirrhosis shows a significant correlation
between APRI and HVPG. The cut-off of APRI is
0.876, and this cut-off has a tremendous positive
predictive value (PPV) as high as 94% to predict
HVPG > 12 mmHg with moderate accuracy
(73%). APRI can be used as a predictor for
severe esophageal varices. The value of APRI
> 1.4 demonstrated sensitivity of 93.9% and
specificity of 60% as a reference of index value
for early intervention in patients with severe
esophageal varices.25 Cho EJ, et al. reported the
accuracy of several biomarkers for assessing
CSPH and esophageal varices in patients with
liver cirrhosis caused by alcohol consumption. In
their study, FIB-4 with cut-off 4.1 to detect CSPH
had sensitivity of 70%, specificity of 42.3%,
PPV of 13.5%, and NPV 59.2% with area under
the curve (AUC): 0.65 (95% CI: 0.5-0.8).28 This
study showed that FIB-4 had low accuracy for
assessing CSPH or even esophageal varices. The
limitation of APRI and FIB-4 is the value of these
diagnostic modalities is dominantly influenced
by aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) by the degree of
inflammation, such as in acute hepatitis or acute
on chronic liver failure (ACLF).27 Due to its low
sensitivity, specificity, and positive predictive
value compared to endoscopic examination,
APRI is not recommended as an alternative
examination for esophageal varices screening.29
Imaging Modalities
Several imaging modalities can be used to
diagnose and evaluate portal hypertension,
such as abdominal ultrasonography
(Abdominal US), magnetic resonance
imaging (MRI), computed tomography (CT-
scan), and transient elastography.30
• Abdominal US
Abdominal US is a non-invasive examination
for patients with chronic liver disease and
liver cirrhosis. Abdominal US is considered
as a more cost-effective method with
less adverse events in comparison to CT-
scan and abdominal MRI to assess portal
hypertension and liver fibrosis. Abnormal

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findings that support the diagnosis of

CSPH are the signs of liver cirrhosis,
splenomegaly, ascites, portal vein dilatation,
splenic vein or mesenteric vein dilatation,
portosystemic collateral (recanalization
of the paraumbilical vein, spontaneous
splenorenal circulation, and the dilatation of
gastric vein), venous return of portal vein,
and reduced velocity of hepatofugal portal
venous blood flow.29 Abdominal US can
also be used for blood flow identification in
hepatic artery, hepatic vein, and portal vein.
An example of abdominal US image with Figure 3. Abdominal ultrasound image of a
patient with portal hypertension.31
M-mode in the spleen of patients with portal
hypertension is attached below. The figure
also shows prominent varices at the posterior
Several parameters of Doppler US that are
side of the spleen (Figure 3).31 Hepatic vein
used as diagnostic parameters are blood flow
blood flow wave can be used as a predictor
velocity, flow direction, damping index,
to assess the severity of portal hypertension
intraparenchymal splenic artery resistance
because of its clinical association with
index (SA-RI), superior mesenteric artery-
HVPG. Nevertheless, abdominal US also
pulsatility index (SMA-PI), and right
has several limitations, such as operator-
interlobar renal artery resistive index (RRA-
dependent, variability between intra- or even
RI)31 (Table 4).
interobserver, influence of inspiration and
expiration towards the results, as well as the • MRI and CT-scan
presence of gas, ascites, and obese condition These modalities can be used as a standard
which may also influence the validity of the method for diagnosing hepatocellular
results.29 carcinoma in patients with liver disease,

Table 4. Summary of studies which evaluated diagnostic performance of Doppler parameters in portal hypertension.
Number
Study of Etiology Parameters Cut-Off Diagnosis Se/Sp/PPV/NPV AUROC
Subjects
Blood flow
12.8
velocity Decompensation 68/75/68/75 0.73895
Kondo, cm/s
236 Mixed
et al.32
Flow Hepato- Prognosis
21.8/99.3/70.6/60.6 -
direction fugal
Severe portal
hypertension
Kim, et Damping
76 Mixed 0.6 (HVPG > 12 75.9/81.8/91.1/58.1 0.860
al.33 index
mmHg)

Severe Portal
SA-RI 0.6 Hypertension 84.6/70.4/80/76 0.82

Vizzutti, Hepatitis Severe Portal

66 SMA-PI 2.7 Hypertension 85.7/65.2/79/75 0.78
et al.34 C Viral

Severe Portal
RRA-RI 0.65 Hypertension 79.5/59.3/74/66 0.78

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Juferdy Kurniawan
including liver cirrhosis. However, the
accuracy of CT-scan and MRI in diagnosing
early stages of liver cirrhosis are limited.
However, MRI and CT-scan can still be used
if complications, such as ascites and portal
vein dilatation, occur. MRI and CT-scan
are also considered as the best diagnostic
modalities to find morphological changes in
hepatic and adjacent tissues. Both modalities
can also detect hemodynamic changes. With
multidetector CT, the scanning process
can achieve submillimeter size, and thus,
enabling the device to assess portosystemic
collateral condition. The sensitivity and
specificity of both modalities are 93% and
80%, respectively, for detecting esophageal
varices. Another application of CT-scan
is esophagography CT multidetector.
Esophagography needs air insufflation into
the esophagus via an oral tube and patient is
requested to ingest a capsule. Hitherto, these
supporting examinations are still considered
as safe and reliable. Therefore, these methods
can be used as alternative examinations,
especially for patients with contraindications
to esophagogastroduodenoscopy.35
• Magnetic Resonance Elastography (MRE)
MRE is a method to assess liver elasticity
quantitatively. MRE can distinguish different
body tissues with higher accuracy compared
to other modalities, such as abdominal US,
CT-scan, and conventional MRI. Another
advantage in using this modality is lack
of influence of body composition, lack of
influence of the ability of operator, and
the ability to assess liver function more
thoroughly. Nonetheless, MRE is still
considered as an expensive modality, and
thus, making it less available for routine
diagnostic modality.29
• Transient Elastography
According to recent studies, progressivity
of liver fibrosis is associated with
increased liver stiffness. Transient
elastography (Fibroscan ) is the most
common method for assessing liver
stiffness.30 Liver stiffness showed good
correlation with HVPG (r= 0.55-0.86;
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Acta Med Indones-Indones J Intern Med
p < 0.04), and hence, making it also
possible to detect CSPH. The Baveno
VI consensus recommended cut-off
value of > 21 kPa to suspect CSPH in
patients with compensated advanced
liver disease caused by viral infection.30,35
In line with progression of portal
hypertension, there will also be a
progressive increase in spleen size due to
venous return to the spleen, hyperplasia,
angiogenesis, and fibrogenesis. 30 In
another study, spleen stiffness also
showed good correlation with the
findings of transient elastography and
HVPG (r=0.78; p < 0.05). A study in
patients with liver cirrhosis caused
by hepatitis C infection demonstrated
threshold value of liver stiffness < 40
kPa to exclude the probability of CSPH.
This value had sensitivity as high as
98%. Moreover, threshold value of ≥ 53
kPa to suspect CSPH had specificity of
97%.36 However, measurement of spleen
stiffness with transient elastography also
showed failure rate as high as 15-20%.1
Invasive Examination
HVPG Measurement
Measurement of HPVG is considered
as the gold standard examination for portal
hypertension. HVPG is the difference between
WHVP and FHVP (Table 5). WHVP is measured
by occluding hepatic vein until blood flow
stopped and stasis occurred. Hepatic vein
occlusion can be performed through distention
of hepatic veins with a balloon catheter, while
non distended balloon catheter can be used for
measuring free hepatic venous pressure (non-
occlusion). In patients with liver cirrhosis,
HVPG is also a predictor of survival and risk of
decompensation. Meanwhile, in decompensated
patients, HVPG can be used to assess the risk
of mortality. Furthermore, HVPG measurement
can also be used as an indicator of prognosis
and therapeutic efficacy in patients with portal
hypertension, for instance, in the usage of
propranolol.24
Continuous monitoring of HVPG changes
should be performed due to its association with
Vol 54 • Number 2 • April 2022 National Consensus on Portal Hypertension Management in Indonesia
clinical outcomes of the patients. Previous
studies indicated that if HVPG value could
drop for more than 20% from baseline value or
decrease until it reaches < 12 mmHg, then the risk
of rebleeding, ascites, encephalopathy, and death
will also decrease significantly. In compensated
liver cirrhosis, > 10% decrease in HVPG from
baseline reduces the risk of esophageal varices,
variceal bleeding, and death.37 However, to date,
non-invasive examination with decent accuracy
in diagnosing changes of HVPG is still not
available yet. A retrospective study by Choi SY,
et al. in 23 liver cirrhosis patients with serial
HVPG measurement showed that changes in
liver stiffness level measured with shear-wave
elastography correlated with HVPG changes.
However, further studies with larger sample
size are still necessary to validate the benefit
of monitoring HVPG with liver elastography.38
More data are also required to support the
validity and applicability of HVPG monitoring
in patients who receive primary prophylaxis.39
Esophagogastroduodenoscopy (EGD)
EGD is a standard procedure to diagnose
gastroesophageal varices. EGD has also been
demonstrated to be useful in predicting bleeding
risk. Location, size, and characteristics of
esophageal varices can be assessed with
EGD (Table 5). However, there are still
several concerns on the use of EGD due to its
invasiveness, high cost, and complications, such
Table 5. Summary of non-invasive and invasive diagnostic modalities for patients with portal hypertension in liver cirrhosis.40
Diagnostic Methods
Non-Invasive
Ultrasonography (USG)
Liver
Portal Vein
Spleen
Portosystemic Collaterals, ascites
CEUS (Contrast-Enhanced Ultrasound)
Examination
Cross-sectional imaging
Elastography
Liver Stiffness
Spleen Stiffness
Invasive
Liver Biopsy
Liver Hemodynamic
Endoscopy
as infection, bleeding and perforation.6,36
EGD screening is recommended for all liver
cirrhotic patients at the time when diagnosis of
cirrhosis has been established. After endoscopic
screening, patients with moderate or large
varicose veins should be treated to prevent
bleeding episodes, while other patients, who do
not have any history of prior esophageal varices
and who have not received any therapy for the
etiology of their liver cirrhosis, have to undergo
periodical surveillance endoscopic examinations
every two years. Meanwhile, patients, who
have received therapy for the etiology of their
liver cirrhosis, are recommended to have the
surveillance every three years. If the initial
screening reveals small esophageal varices, it is
recommended to repeat the endoscopy one year
afterwards if no etiologic therapy has been given
or after two years if etiologic therapy has been
given. If the patient shows any clinical signs of
decompensation, it is advisable to perform EGD
examination again.6
Liver Biopsy
Liver biopsy is a gold standard examination
for diagnosing liver cirrhosis. Liver biopsy is
usually followed by evaluation with scoring
system to determine the degree and stages of
chronic liver disease. However, this examination
is invasive, thus the usage is limited. The risk
of error in tissue sampling may also affect the
results of examination (Table 5).35
Findings
Irregular surface, inhomogeneous, focal lesion in liver
Dilatation, thrombosis +/-
Splenomegaly
+
Slow enhancement of periportal/heterogeneous/ homogenous
Better characterization of liver focal lesion
↑
↑
Fibrosis and changes in liver architecture
Normal FHVP, WHVP↑, HVPG↑, hyperdynamic circulation
Esophageal varices and hypertensive gastropathy are more commonly
observed, whereas gastric varices are less common to be found
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MANAGEMENT > 1.1 g/dL indicates the involvement of portal

Effective reduction of portal pressure can
reduce the incidence of complications and
improve survival in patients with cirrhosis.
Therapeutic efficacy on portal pressure can be
assessed indirectly through clinical outcomes,
such as the incidence of variceal bleeding, or
directly through HVPG assessment. Achieving
a pressure gradient of less than 12 mmHg or
a 20% decrease from baseline is associated
with decreased incidence of significant
complications.11
Ascites
The presence of ascites is one of the poor
prognostic markers in cirrhotic patients, with
a reduction in 5-year survival from 80% in
compensated cirrhotic patients to 30% in
decompensated cirrhotic patients with ascites.
The main pathophysiology of ascites is sodium
retention by the kidneys due to activation of the
sodium retention system, such as RAAS and
sympathetic nervous system. Decreased effective
volume due to vasodilation of splanchnic arteries
can lead to a positive fluid balance, causing an
increase in extracellular fluid volume.5 Ascites
is classified according to the amount of fluid in
the abdominal cavity (Table 6).1,41 Diagnostic
paracentesis is indicated in all patients with
episodes of first, second, or third grade of ascites,
as well as in all patients who require treatment
for complications of cirrhosis. Assessment
of neutrophil levels, total protein, albumin
concentration, and fluid cultures should be
performed. Cultures with at least 10 mL of ascites
fluid were performed to exclude the possibility of
bacterial peritonitis. In cases where the cause of
ascites is unclear, serum ascites albumin gradient
(SAAG) calculation can be helpful where SAAG
hypertension in ascites formation.5
Ascites without Complications
Ascites without complications is defined as
ascites without infection or refractory episodes
or HRS. Generally, the management of ascites
consists of sodium restriction, administration of
diuretics, and therapeutic paracentesis. Sodium
intake is maintained between 80-120 mmol/day,
which is equivalent to 4.6-6.9 grams of salt/
day. A diet with very low sodium intake (<40
mmol/day) should be avoided because it can
cause complications when administered together
with diuretics and interfere with the nutritional
status of the patient. Fluid restriction is only
recommended in hypervolemic hyponatremic
patients with sodium levels <130 mEq/L with
ascites and/or edema.5,42
Meanwhile, the goal of diuretic administration
is to achieve a negative fluid balance, which
can be shown from the weight loss. The
effectiveness of diuretic administration in
controlling ascites is about 90% in patients
without renal impairment.42 Ideally, weight loss
must not exceed 500 mg/day in patients without
peripheral edema and must not exceed 1000 mg/
day in patients with peripheral edema to avoid
contractions in plasma volume, which may lead
to renal failure or hyponatremia.43 In cirrhotic
patients, secondary hyperaldosteronism plays a
major role in sodium retention. Hence, drugs that
work as anti-mineralocorticoids become drugs of
choice for ascites. The maximum recommended
dose is 400 mg/day. Related with delayed anti-
mineralocorticoid effects, the dose of these drugs
should not be increased in less than 72 hours.5
On the other hand, in patients with long-standing
ascites, sodium reabsorption in the proximal

Table 6. Management of ascites according to the severity grading.5

Classification
1st Grade (mild ascites)
2nd Grade (moderate ascites)
3rd Grade (severe ascites)
Definition
Ascites is only detected through
ultrasonography examination.
Ascites appears as symmetric
abdominal distension.
Ascites appears as a significant
abdominal distention.
Management
No special treatment is required.
Sodium restriction and diuretic administration.
Large volume paracentesis and administration of
albumin (8 gram/L of ascitic fluid that is removed
through paracentesis) followed by sodium restriction
and diuretic administration

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tubule may occur. Therefore, in this group of
patients, strong diuretics (loop diuretics) can
be given. Furosemide can be administered as
an adjunctive therapy by increasing the dose
gradually (starting at 40 mg/day up to 160 mg/
day – increased by 40 mg). In patients with good
compliance, but ascites is still not controlled,
the dosage of diuretic can be increased by
doubling the dose (1:1 ratio) until it achieves
the maximum dose of spironolactone (400 mg/
day) and furosemide (160 mg/day). Once ascites
mobilization is achieved, the dose of diuretic
should be reduced gradually to the lowest dose
needed to control ascites in order to minimize
side effects.42 The side effects that need to be
noticed are fluid and electrolyte imbalances, such
as hyponatremia, dehydration, renal impairment,
hyperkalemia or hypokalemia, and subsequently,
hepatic encephalopathy. Spironolactone also
tends to cause gynecomastia and muscle cramps
in some patients. 5,42
In patients with large or grade 3 ascites, the
first line of treatment is large-volume paracentesis
(LVP) (more than 5 liters) performed in a single
session. It is recommended to perform LVP with
ultrasound guidance to reduce the possibility
of side effects. Taking ascites fluid in large
volume can potentially cause post-paracentesis
circulatory dysfunction (PPCD). The clinical
manifestations can be renal failure, dilutional
hyponatremia, and hepatic encephalopathy. For
this reason, plasma volume expansion at the end
of the paracentesis is necessary. Administration
of plasma expanders, such as dextran-70 (8 g/L
of ascitic fluid taken), polygeline (150 ml/L),
and saline (170 ml/L), has demonstrated similar
efficacy to 20% albumin (8 g/L) if the fluid taken
is less than five liters.42
Refractory Ascites
Refractory ascites is defined as ascites which
cannot be mobilized or recurrent in a short
duration after LVP or without any adequate
response towards pharmacological treatment
(Table 7). Refractory ascites is also one of the
bad prognostic markers in cirrhotic patients,
indicated by approximately 6-months of mean
survival duration. Another term, i.e., recurrent
ascites, is defined as the presence of recurrent
ascites episodes for at least three times in one
year.5,42 Therapeutic LVP is considered as a safe
and effective option for refractory ascites. It is
recommended to stop diuretic administration
when diagnosis of refractory ascites has been
determined. Diuretic administration can be
considered again if it can be tolerated by the
patient with renal sodium excretion > 30 mmol/
day.42
Aside from LVP, several other therapeutic
options can be considered in managing refractory
ascites. The first option is by creating Transjugular
Intrahepatic Portosystemic Shunt (TIPS), where
intrahepatic stent will be placed between hepatic
vein and portal vein for portal decompression and
for stimulating peripheral artery vasodilatation
in short time.42 The most common complication
of TIPS is hepatic encephalopathy, especially
with the use of bare stent graft.44,45 The rate
of complications decreased by 18% with the
use of polytetrafluoroethylene-covered stent.46
In general, TIPS is not recommended in the
presence of serum bilirubin level higher than
3 mg/dL, platelet counts < 75,000, hepatic
encephalopathy grade > 2 or chronic, active
infection, progressive renal dysfunction, severe
systolic or diastolic dysfunction, or pulmonal
hypertension.5 The use of continuous drainage
catheter can be considered if TIPS cannot be
performed. Peritoneal catheter can be placed
percutaneously by using tunnel or non-tunnel
technique, depends on the types of catheters. It
is important to remember that the use of catheter
for more than 12 weeks has been associated with
significantly higher risk of infection.47,48 Hitherto,
additional administration of alpha-adrenergic
agonists, such as midodrine or clonidine, has not
been recommended as a therapeutic option for
refractory ascites.5,42
Hepatic Hydrothorax
Hepatic hydrothorax is defined as
accumulation of transudate fluid inside the
pleural cavity (usually more than 500 mL) in
decompensated cirrhotic patients without any
other cardiopulmonary comorbidities or pleural
abnormalities.49,50 The presence of intrathoracic
negative pressure and intraabdominal positive
pressure may lead to ascitic fluid movement
through diaphragm minor openings. These
openings are usually located on the tendinous
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Table 7. Definition and diagnostic criteria of refractory ascites.5

Definition
Diuretic-resistant ascites Ascites which cannot be mobilized or recurrent ascites in short duration and cannot
be prevented due to inadequate responses with sodium restriction and diuretic
administration.
Diuretic-intractable ascites Ascites which cannot be mobilized or recurrent ascites in short duration and cannot
be prevented to avoid diuretic complications, and thus, leading to inability to achieve
the most effective dose of diuretic.
Diagnostic Criteria
Duration of therapy When the patient has already been in intensive diuretic therapy (spironolactone 400
mg/day and furosemide 160 mg/day) for at least one week and sodium restriction (<
90 mmol/day).
Inadequate response Mean weight loss < 800 gram after four days and lower urinary sodium excretion
compared to sodium intake.
Early recurrence Re-appearance of grade 2 or 3 ascites within 4 weeks after early mobilization.
Diuretic complications -- Hepatic encephalopathy caused by diuretics (excluding other possible causes).
-- Renal dysfunction caused by diuretics: increased serum creatinine for > 100%
until > 2 mg/dL (177 umol/L).
-- Hyponatremia caused by diuretics: decreased serum sodium level > 10 mEq/L
until < 125 mEq/L.
-- Hypo- or hyperkalemia caused by diuretics: changes of serum potassium level
until < 3 mEq/L (hypokalemia) or > 6 mEq/L (hyperkalemia).
-- Unexplained muscle cramps.

part of diaphragm, which is usually covered
with pleuroperitoneum. Hepatic hydrothorax is
also considered as a marker of bad prognosis
with approximately 8-12 months of mean
duration of survival.51,52 In hepatic hydrothorax,
pleural effusion is usually found in the right
pleura with transudate characteristic. Other
common laboratory findings from pleural fluid
analysis include < 250/mm3 polymorphonuclear
leukocytes (PMN) count, protein < 2.5 gram/
dL, ratio between protein in the pleural fluid/
serum protein < 0.5 with the gradient of serum
albumin-pleural fluid > 1.1 gram/dL, and ratio
between LDH in pleural fluid/serum LDH <
2:3. In the presence of spontaneous bacterial
empyema, diagnosis can be established when
positive result is obtained from pleural fluid
culture accompanied with increased neutrophil
count by > 250/mm3 or negative result from
pleural fluid culture accompanied with increased
neutrophil count by > 500/mm3.5,50
The first line management in hepatic
hydrothorax is treating ascites by administering
diuretics and/or LVP. Therapeutic thoracocentesis
is indicated in refractory hepatic hydrothorax.
To prevent the risk of re-expansion pulmonary
edema, it is recommended to perform
thoracocentesis without exceeding 2 liters of
fluid in one session.50 Nevertheless, due to the
increased risk of pneumothorax, pleural and/
or soft tissue infection, and bleeding, liver
transplantation remains as the best therapeutic
option for refractory hepatic hydrothorax. TIPS
insertion has a role as a bridging therapy prior to
liver transplantation. In conditions where liver
transplantation or TIPS cannot be conducted,
pleurodesis can be considered with success rate
as high as 72%.53 In cirrhotic patients with normal
renal function and well-localized diaphragmatic
defect, thoracoscopic procedure using mersilene
mesh can also be considered.54
Hyponatremia
Hyponatremia is defined as serum sodium
level < 130 mEq/L, which can be found in
approximately 22% of cirrhotic patients. In liver
cirrhosis, most hyponatremia events are caused
by dilutional hypervolemia due to increased
extracellular fluid volume. Vasodilatation of
splanchnic artery in cirrhosis also contributes to
decreased effective blood volume. Consequently,
RAAS will be activated, leading to excessive
release of antidiuretic hormone and, ultimately,
reduced fluid excretion.55 In patients without
ascites and edema, usually hyponatremia
hypovolemia is observed.5 Hyponatremia has
also been associated with worse prognosis,
shown by its role in Model for End-Stage

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Liver Disease-Natrium (MELD-Na) scoring.
Utilization of MELD-Na scoring system is
correlated with reduced mortality rate by
up to 7% during waiting period for liver
transplantation, in comparison to conventional
MELD scoring system.56
Hyponatremia needs to be treated when
serum sodium level reaches less than 130 mEq/L.
Plasma volume expansion with saline solution
is necessary in hyponatremia hypovolemia
condition. On the contrary, the goal of therapy
for hyponatremia hypervolemic is negative fluid
balance, for instance through non-osmotic fluid
restriction. Administration of hypertonic sodium
chloride solution can improve hyponatremia in
decompensated cirrhotic patients with special
precautions in fluid overload condition. It
is recommended to avoid administration of
hypertonic sodium chloride solution exceeding 8
mEq/L in 24 hours to reduce the risk of osmotic
demyelination syndrome. Liver transplantation
remains as the definitive treatment for chronic
liver disease with hyponatremia. Meanwhile,
the use of intravenous albumin or selective
antagonist of arginine-vasopressin V2 receptor
in collecting duct still needs further studies.5,57,58
Spontaneous Bacterial Peritonitis (SBP)
SBP is defined as bacterial infection in ascitic
fluid without any clear source of intraabdominal
infection. Bacterial translocation from the gut,
modified systemic defense mechanism, as well as
deficiency of antimicrobial activity in ascitic fluid
are the key factors in the pathogenesis of SBP. In
liver cirrhosis, bacterial translocation often occurs
due to bacterial overgrowth caused by disturbed
transition inside the colon. Portal hypertension
causes increased colon permeability through
hypoxic mucous, oxidative stress, splanchnic
vascular stasis, and congestion of the mucous
layer of the colon. Disturbance in phagocytic
activities of reticuloendothelial system represents
the changes in systemic immunity. Moreover,
low C3 level and low opsonization activity in
ascitic fluid also contribute to low antimicrobial
activity.50 Diagnosis of SBP is established if
increased absolute PMN count > 250 cells/mm3
is obtained from ascitic fluid analysis. This
condition is known as neutrocytic ascites if there
is no evidence of intraabdominal infection. If
this result is accompanied with positive culture
of ascitic fluid, then the condition is known
as culture-positive neutrocytic ascites. In
neutrocytic ascites with negative culture of ascitic
fluid, the condition is called culture-negative
neutrocytic ascites. If positive culture of ascitic
fluid is obtained without neutrocytic ascites,
then the condition is called bacterascites.59 The
most common etiologic bacteria are Eschericia
coli, Klebsiella pneumoniae, and Streptococcus
pneumoniae.42
Prognosis of patients with SBP is very
atrocious with in-hospital mortality rate as
high as 20%-40%. Therefore, early diagnosis
and adequate treatment are highly compulsory
for improving the prognosis. Empirical
antibiotic therapy should be administered as
soon as the diagnosis has been established,
adjusted according to the possible etiologic
microorganisms, severity of infection,
and local antibiotic resistance profiles. In
polymicrobial bacterascites, the third generation
of cephalosporin can be given with additional
anti-anaerobic therapy, such as metronidazole.60
Administration of the third generation of
cephalosporin demonstrated resolution of
infection in 77%-98% of the patients.61 As an
alternative, amoxicillin/clavulanate also showed
comparable resolution of infection and mortality
rate with administration of cefotaxime, although
higher number of drug-induced hepatitis was
also observed. 62,63 Piperacillin/tazobactam
or carbapenem also becomes drug of choice
in nosocomial SBP or in regions where high
level of resistance towards the third generation
of cephalosporin is found. 42 Tigecycline or
combination of tigecycline and carbapenem
can be administered when carbapenemase-
producing and carbapenem-resistant non-
carbapenemase-producing Enterobacteria
are suspected as the etiologic agent. In severe
infection due to carbapenem-resistant and
quinolone-resistant Pseudomonas aeruginosa,
combination of amikacin and tobramycin or
colistin-carbapenem/ceftazidime can be an
option. If vancomycin-resistant Enterococci is
suspected as the etiologic agent, administration
of linezolid, daptomycin, and tigecycline can
be conducted. It is also critical to perform
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Juferdy Kurniawan
antibiotic de-escalation based on the results of
microorganism culture to minimize the risk of
antibiotic resistance.64,65 It is recommended to
evaluate the effect of antibiotic as early as 48
hours after the initial administration. Failure of
the first-line antibiotic must be suspected when
there is no improvement of clinical symptoms,
or the absence of decreased white blood cells
count by at least 25% in 48 hours.5
Aside from treatment, antibiotics also
have a prominent role as prophylaxis of SBP.
There are three populations who are deemed
to have high risk of SBP, i.e., patients with
acute gastrointestinal bleeding, patients with
low protein level (< 1 gram/dL) in ascitic
fluid without any history of prior SBP, and
patients with history of prior SBP. Patients with
history of prior SBP demonstrated cumulative
recurrence rate in one year as high as 70%.
Long-term oral administration of norfloxacin
(400 mg/day) showed significant decrease of
recurrence rate by 48%.5 When norfloxacin is
not available, 500 mg ciprofloxacin daily can be
given as primary or secondary prophylaxis. Other
alternative antibiotics are 960 mg trimethoprim-
sulfamethoxazole daily per oral, 250 mg
levofloxacin daily per oral, or intravenous 1 gram
ceftriaxone daily.66-68 Primary and secondary
prophylaxis are recommended to be administered
until ascites is resolved or liver transplantation
Figure 4. Management of renal dysfunction in cirrhosis (Adapted from [70]).
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Acta Med Indones-Indones J Intern Med
can be performed or death.68
Renal Dysfunction
Acute Kidney Injury (AKI)
In liver cirrhotic patients, renal dysfunction
is defined as a condition where serum creatinine
level is at least 1.5 mg/dL or increased serum
creatinine level by > 50% from the baseline with
glomerular filtration rate (GFR) index < 40 ml/
min/1.73 m2. Renal dysfunction can be found
in the form of AKI or chronic kidney disease
(CKD). In liver cirrhotic patients, AKI can be
caused by diuretics, beta-blockers, vasodilator
agents, Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), and other nephrotoxic drugs. In the
condition of infection-induced AKI or AKI stage
> 1A and the cause of AKI cannot be determined
clearly, the intravenous administration of 20%
albumin is recommended (1 gram/kgBW/day,
maximum dose: 100 gram) for two consecutive
days. For patients with AKI and grade 3 ascites,
therapeutic paracentesis can be performed,
and then followed by intravenous albumin
administration. Other therapeutic options include
renal replacement therapy (RRT) or kidney
transplantation (Figure 4).69,70
Hepatorenal Syndrome (HRS)
HRS can be present with (HRS-AKI)
or without AKI (HRS-NAKI). 69,71 HRS is
mainly caused by renal hypoperfusion due to
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synergistic work between inflammation and
microvascular disturbances in end-stage chronic
liver disease. Both factors may amplify signals
elicited by Pathogen-Associated Molecular
Patterns (PAMPs) and Damage-Associated
Molecular Patterns (DAMPs) on epithelial
cells of proximal tubules. This process will
lead to metabolic down-regulation mediated by
mitochondria. Additionally, signal transduction
will also change the priority of cell functions
into prioritizing cell viability. RAAS activation
and decrease of GFR also happen because of
increased sodium chloride in macula densa. If
the patient also has cholestasis, renal dysfunction
will also be worsened since bile salts may trigger
inflammation, disrupt circulation, and damage
renal tubules.72
The first line of pharmacological management
in HRS is vasoconstrictor and albumin (Figure
4).70 An example of vasoconstrictor is terlipressin
as a vasopressin analogue. Terlipressin also plays
a role in decreasing stroke volume of patients
with HRS. On the other hand, albumin has
antioxidant and anti-inflammatory traits with
recommended dose of 20-40 gram/day (adjusted
according to the central venous pressure (CVP)
measurement). Albumin administration is
maintained until complete resolution (serum
creatinine level < 1.5 mg/dL) for maximum
duration of 14 days or partial resolution
(decrease of serum creatinine level by > 50%)
or if no clinical changes are observed. It is also
recommended to administer 1.5 gram/kgBW
of albumin on the first day within 6 hours after
diagnosis of SBP is confirmed and 1 gram/
kgBW of albumin on the third day, in order to
prevent AKI in patients with SBP.5 Other choices
of vasoconstrictors include noradrenaline,
midodrine, and octreotide (Table 8).73,74 TIPS
placement can be considered in both HRS-AKI
and HRS-NAKI, although its use is still limited
and contraindicated in patients with severe liver
failure.75 RRT must be considered in patients with
AKI, especially if there is acid-base imbalance or
severe and/or refractory electrolyte imbalance.
Continuous RRT has also demonstrated better
contribution towards stability of heart and
blood vessels compared to hemodialysis. 71
Nonetheless, the best definitive therapy for HRS
is liver transplantation. Simultaneous Liver-
Kidney Transplantation (SLK) is indicated in
patients with liver cirrhosis and CKD with the
following conditions:5
• Estimated GFR (with Modification of
Diet in Renal Disease equation) < 40
mL/min/1.73 m 2 or GFR measured by

Table 8. Recommended doses of vasoconstrictors in the management of HRS.5,73,74

Terlipressin Noradrenaline Midodrine Octreotide
Recommended Initial dose for Continuous infusion Initial dose: 7.5 Subcutaneous
dose intravenous bolus: dose: 0.5 – 3 mg/ mg/8 hours. dose: 50 ug/hour.
0.5-1 mg every 4-6 hour.
hours. OR Maximum dose: 15 Continuous infusion
OR Initial dose: 0.5 mg/ gram/8 hours. dose: 100-200 ug/8
Continuous infusion hour, increased hours.
dose 2 mg/day. by 0.5 mg/hour
After 2 days, every 4 hours until
the dose can be maximum dose of
increased into 3 mg/hour (only
maximum dose of if at least one of
12 mg/day. these targets are
not achieved:
OR increase of MAP by
minimum 10 mmHg
Fixed dose (1 mg or increase urinary
every 8-12 hours), output > 200 mL/4
increased by 2 mg hours).
every 4 hours.
Duration Administered until Administered until Administered until Administered until
serum creatinine serum creatinine serum creatinine serum creatinine
level < 1.5 mg/dL or level < 1.5 mg/dL or level < 1.5 mg/dL or level < 1.5 mg/dL or
maximum duration maximum duration maximum duration maximum duration
of 14 days. of 14 days. of 14 days. of 14 days.

339
Juferdy Kurniawan
iothalamate clearance < 30 ml/min/1.73 m2.
• Proteinuria > 2 gram/daily.
• Histopathological findings of the kidney:
more than 30% glomerulosclerosis or more
than 30% interstitial fibrosis.
• Hereditary metabolic disorders.
SLK is also indicated for patients with liver
cirrhosis and AKI without any improvement (e.g.,
HRS-AKI which does not show any improvement
after pharmacological management) with the
following conditions:5
• AKI on RRT for > 4 weeks, or
• Estimated GFR < 35 mL/min/1.73 m2 or
measured GFR < 25 mL/min/1.73 m2 for at
least 4 weeks.
Acute Variceal Bleeding
Acute variceal hemorrhage (AVH) is defined
as variceal bleeding in patients with confirmed or
suspected portal hypertension, with the presence
of hematemesis and/or ongoing melena within 24
hours upon admission. Generally, the timeframe
Figure 5. Treatment algorithm of acute gastrointestinal bleeding in liver cirrhosis (Adapted from [5]).
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Acta Med Indones-Indones J Intern Med
of AVH episode is 48 hours. The main principle
of AVH treatment is preventing recurrent
bleeding episode and death (Figure 5).35 Fluid
replacement therapy must be initiated as soon as
possible to return hemodynamic stability. The
recommended fluids are crystalloid or colloid.
To date, starch is not recommended as an option
for fluid replacement therapy. Administration of
restrictive blood transfusion can be done if the
patient had low hemoglobin level (< 7 gram/dL)
with target of hemoglobin level post-transfusion:
7-9 gram/dL.5,73
Currently, non-selective beta-blocker
(NSBB) has a role as primary prophylaxis,
while Endoscopic Band Ligation (EBL) plays
a role as secondary prophylaxis (Table 9)76 to
prevent variceal bleeding in high-risk cirrhotic
patients. Propranolol and nadolol manage portal
hypertension by decreasing stroke volume
and splanchnic blood flow. Simultaneously,
the effect of alpha-1 adrenergic receptor also
triggers splanchnic vasoconstriction, and thus,
Vol 54 • Number 2 • April 2022 National Consensus on Portal Hypertension Management in Indonesia

Table 9. Prophylaxis for preventing recurrent variceal bleeding.5-6,76

Therapy Recommended Doses Therapeutic Goals Maintenance Therapy
Propranolol 20-40 mg (twice daily) g adjust the Resting heart rate: 55-60 Continue therapy for
dose in 2-3 days. beats/minute. maintenance.

Maximum daily dose: 320 mg/day in Systolic blood pressure

patients without ascites or 160 mg/day should not be lower than 90
in patients with ascites. mmHg.
Nadolol 20-40 mg once daily. Resting heart rate: 55-60 Continue therapy for
beats/minute. maintenance.
Dose adjustment: 160 mg/day in
patients without ascites or 80 mg/day Systolic blood pressure
in patients with ascites. should not be lower than 90
mmHg.
Carvedilol Initial dose: 6.25 mg once daily. After Systolic blood pressure Continue therapy for
3 days, the dose can be increased to should not be lower than 90 maintenance.
6.25 mg (twice daily). mmHg.

Maximum dose: 12.5 mg/day (in Decreased heart rate should

patients with persistent arterial
hypertension, the dose can be
increased until 12.5 mg twice daily or
25 mg/day).
EBL Every 2-8 weeks until varices can be
eradicated.
not be a reference for dose
titration.
Until varices can be
eradicated
The first EGD should be
performed within 3-6 months
after varices has been
eradicated and every 6-12
months afterwards.

decreasing portal pressure. Carvedilol can also
be an alternative to lower intrahepatic resistance
and porto-collateral blood flow.5,6 NSBB must
be halted when severe hyponatremia occurs
(serum sodium level < 130 mEq/L), or if
the mean of MAP is low (< 65 mmHg), or if
the stroke volume is low with systolic blood
pressure < 90 mmHg, or if serum creatinine
level is increased by > 1.5 mg/dL. Carvedilol
or high-dose NSBB is also recommended to be
avoided in severe or refractory ascites. In the
condition of intolerance towards NSBB, EBL can
be performed. Combination of NSBB and EBL
can also be an option for secondary prophylaxis
with higher therapeutic efficacy in comparison
to monotherapy. The therapeutic efficacy of this
combination is also comparable with TIPS in
preventing bleeding episode.5,73
Aside from fluid replacement, vasoactive
agents and antibiotics also need to be administered
as early as possible to control active bleeding and
increase the possibility of survival. Recommended
vasoactive agents include terlipressin,
somatostatin, and octreotide (Table 10).5 Bolus
of intravenous somatostatin or octreotide can
still be administered if bleeding episode still
occurs. When AVH diagnosis has been confirmed,
vasoactive agents can be continued for 5 days
to prevent early recurrent bleeding (Table 11).77
Shorter duration of vasoactive administration
(48-72 hours) is contemplated when the bleeding
episode is not too severe. Endoscopic examination
is recommended to be conducted as soon as
blood volume resuscitation and hemodynamic
stability have been achieved (within 12 hours
after hospital admission).78 Combination between
endoscopic therapy and vasoactive agent has
more efficacy compared to monotherapy due
to local hemostatic effect from endoscopic
therapy and portal pressure lowering effect from
vasoactive agents.79 Cyanoacrylate injection is
currently recommended as an endoscopic therapy
for patients with gastric varices (cardio-fundal
varices).80 In addition, fluoroscopy-guided coil
insertion and/or cyanoacrylate injection can also
be done to treat fundal varices (Table 12).5,77,81
It is also important to remember that
variceal bleeding can lead to several morbid
complications, such as bacterial infections,
hepatic encephalopathy, and renal dysfunction.
Antibiotic prophylaxis is recommended to lower
the incidence of secondary infection, control

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Juferdy Kurniawan Acta Med Indones-Indones J Intern Med

Table 10. Recommended doses of vasoactive agents for acute variceal hemorrhage management.5
Therapy Recommended Doses Duration of Therapy
Initial IV bolus 50 ug (can be repeated within the first one
Octreotide hour if bleeding persists). 2-5 days.
Continuous infusion: 50 ug/hour.
Initial IV bolus 250 ug (can be repeated within the first one
Somatostatin hour if bleeding persists). 2-5 days.
Continuous infusion: 250-500 ug/hour.
Within the first 48 hours: 2 mg intravenous until bleeding
can be controlled.
Terlipressin 2-5 days.
Maintenance dose: 1 mg intravenous every 4 hours to
prevent recurrent bleeding.

Table 11. Clinical definitions of acute and recurrent variceal bleeding.77

Clinical Conditions Timeframe from T0 Subtypes Timeframe from T0

Active (based on endoscopic
Acute variceal bleeding 48 hours 48 hours
examination)
Inactive (based on
48 hours
endoscopic examination)
Recurrent bleeding After 48 hours Very early recurrent bleeding 48-120 hours
Early recurrent bleeding 6-42 days
Late recurrent bleeding After 42 days

Table 12. Classification, prevalence, and bleeding risk of gastric varices.77

Relative Risk of Bleeding
Types Definition
Frequency Without Therapy
GOV1 Esophageal varices extended until lower cardia towards minor 70% 28%
curvature.
GOV2 Gastroesophageal varices extended until lower cardia towards 21% 55%
fundus.
IGV1 Isolated varices on fundus. 7% 78%
IGV2 Isolated varices in locations other than gaster. 2% 9%

the bleeding, and increase life expectancy.6 The
first line antibiotic for patients with advanced
cirrhosis, who are consuming quinolone as a
prophylaxis with history of hospitalization in
a healthcare center with high prevalence of
quinolone resistance, is intravenous ceftriaxone
(1 gram/day) for 7 days. Oral quinolone can be
given if the patient cannot tolerate ceftriaxone
(Table 13).66 In 10-15% cases, where AVH
still persists or becomes recurrent despite
the administration of vasoactive agents and
antibiotic prophylaxis combined with EBS, TIPS
should be considered as a salvage therapy.6 If
TIPS cannot be performed, endoscopic therapy
can be conducted for the second time with
optimalization of vasoactive drugs and 2-fold
increase of somatostatin dose and/or replacement
with terlipressin. Balloon tamponade or self-
expanding esophageal stents can also be placed
as an alternative bridging therapy.82

Table 13. Recommended doses of antibiotic prophylaxis in acute variceal bleeding.5,66,78

Therapy Recommended Doses Duration of Therapy
500 mg per oral twice daily
Ciprofloxacin OR 3-7 days
400 mg intravenous twice daily,
Ceftriaxone 1 gram daily. 7 days

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Vol 54 • Number 2 • April 2022 National Consensus on Portal Hypertension Management in Indonesia
Others
Coagulopathy
Vitamin K deficiency is commonly found
in decompensated cirrhotic patients, which is
affected by a complex mechanism involving
bile salt deficiency, failure in bile salt secretion,
and the use of broad-spectrum antibiotics.
Nowadays, vitamin K injection 10 mg daily for
3 days is recommended as an adequate option
to treat vitamin K deficiency in decompensated
cirrhotic patients. Prophylactic correction of
prothrombin time with Fresh Frozen Plasma
(FFP) remains controversial due to a significant
number of adverse events, e.g., fluid overload,
exacerbation of portal hypertension, increased
risk of infection, or acute liver injury related
to transfusion. Platelet transfusion can be
considered when platelet count is lower than
50,000/mm3 with platelet count target > 70,000/
mm3. Maintaining low CVP and reducing portal
pressure can also be helpful during surgical
management. Other options for bleeding
control are topical hemostatic agents, aprotinin,
tranexamic acid, and epsilon caproic amino
acid, which may have a role in controlling local
bleeding. These agents, however, still need
further trials due to higher thrombotic risk.83
Portal Hypertension Gastropathy (PHG)
PHG is commonly found in decompensated
cirrhotic patients. The presence of esophageal
varices and Child-Pugh B or C category can
also predict the incidence of PHG.84 Diagnosis
of PHG can be confirmed by endoscopic
examination, from which mild subtype of
PHG usually appears with mosaic pattern or
may overlap with red signs (severe subtype of
PHG). PHG is usually located on the proximal
part of gaster (fundus and corpus).85,86 In the
progression of chronic liver disease, PHG
plays a critical role since it may cause occult
bleeding, which ultimately leads to chronic
iron deficiency anemia. PHG can also be an
incidental asymptomatic finding in the absence
of gastric or esophageal varices.35 The first line
therapy for chronic bleeding with PHG is NSBB.
Iron supplementation and/or blood transfusion
can also be given according to the clinical
indications.5 In patients with refractory PHG
and compensated cirrhosis, TIPS placement can
improve endoscopic findings, as well as lower the
requirements for blood transfusion. Additionally,
similar to AVH, antibiotic prophylaxis can also
be administered to patients with acute PHG
bleeding.87 An electrosurgical technique, called
Argon Plasma Coagulation (APC), has emerged
as an option to manage bleeding episodes and
devitalization of abnormal tissues. Previous
evidence indicated higher hemoglobin level
and lower blood transfusion requirement after
APC.88,89 Although further validations are still
required, rebamipide has been proposed as a
potential therapeutic agent for PHG due to its
antioxidant effect (free radicals scavenging),
ability to decrease nitration process of tyrosine
residues from Extracellular Signal-Regulated
Kinases (ERK), and mucosal healing capability.90
ACKNOWLEDGMENTS
We want to express our gratitude towards all
chairmen from twenty branches of Indonesian
Association for the Study of the Liver, who had
contributed their time, contribution, and advices
in developing this national consensus.
REFERENCES
1. Turco L, Garcia-tsao G. Portal hypertension:
pathogenesis and management. Clin Liver Dis.
2019;23(4):573–87.
2. Koh C, Heller T. Approach to the diagnosis of portal
hypertension. Clin Liver Dis. 2012;1(5):133–5.
3. Berzigotti A. Advances and challenges in cirrhosis and
portal hypertension. BMC Med. 2017; 15: 200.
4. Tapper E, Parikh N. Mortality due to cirrhosis and liver
cancer in the United States, 1999-2016: observational
study. BMJ. 2018;362:k2817.
5. European Association for the Study of the Liver. EASL
Clinical Practice Guidelines for the management of
patients with decompensated cirrhosis. J Hepatol.
2018;69:406–60.
6. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal
hypertensive bleeding in cirrhosis: Risk stratification,
diagnosis, and management: 2016 Practice Guidance
by the American Association for the Study of Liver
Diseases. Hepatology. 2017;65(1):310–35.
7. Garcia-Tsao G, Bosch J, Haven N, et al. Varices
and variceal hemorrhage in cirrhosis. A new view
of an old problem. Clin Gastroenterol Hepatol.
2016;13(12):2109–17.
8. Procopet B, Berzigotti A. Diagnosis of cirrhosis and
portal hypertension: imaging, non-invasive markers
343
Juferdy Kurniawan
of fibrosis and hepar biopsy. Gastroenterol Rep.
2017;5(2):78–89.
9. Berzigotti A, Bosch J, Escorsell A. Pathophysiology
of variceal bleeding in cirrhotics. Ann Gastroenterol.
2001;14:150–7.
10. Simonetto DA, Liu M, Kamath PS. Portal hypertension
and related complications: Diagnosis and management.
Mayo Clin Proc. 2019;94(4):714–26.
11. García-Pagán J, Groszmann R, Bosch J. Portal
Hypertension. In: Hawkey C, Bosch J, Richter J,
Garcia-Tsao G, Chan F, editors. Textbook of clinical
gastroenterology and hepatology. 2nd. Sussex: Wiley-
Blackwell; 2012.
12. Iwakiri Y. Pathophysiology of portal hyperthension.
Clin Liver Dis. 2014;18(2):281–91.
13. Gulamhusein A, Kamath P. The epidemiology
and pathogenesis of gastrointestinal varices. Tech
Gastrointest Endosc. 2017;19(2):62–8.
14. Atterbury C, Glickman M, Garcia-Tsao G, et al. Portal
pressure, presence of gastroesophageal varices and
variceal bleeding. Hepatology. 1985;5(3):419–24.
15. Ripoll C, Groszmann R, Garcia-Tsao G, et al.
Hepatic venous pressure gradient predicts clinical
decompensation in patients with compensated
cirrhosis. Gastroenterology. 2007;133(2):481–8.
16. Ripoll C, Groszmann R, Garcia-tsao G, et al. Hepatic
venous pressure gradient predicts development of
hepatocellular carcinoma independently of severity
of cirrhosis. J Hepatol. 2009;50(5):923–8.
17. Turco L, Garcia-Tsao G, Magnani I, et al.
Cardiopulmonary hemodynamics and C-reactive
protein as prognostic indicators in compensated and
decompensated cirrhosis. J Hepatol. 2018;68(5):949–
58.
18. Abraldes J, Villanueva C, Bañares R, et al. Hepatic
venous pressure gradient and prognosis in patients with
acute variceal bleeding treated with pharmacologic and
endoscopic therapy. J Hepatol. 2008;48(2):229–36.
19. Busk T, Bendtsen F, Nielsen H, et al. TIMP-1 in
patients with cirrhosis: relation to liver dysfunction,
portal hypertension, and hemodynamic changes. Scand
J Gastroenterol. 2014;49(9):1103–10.
20. Sandahl T, McGrail R, Møller H, et al. The macrophage
activation marker sCD163 combined with markers
of the Enhanced Liver Fibrosis (ELF) score predicts
clinically significant portal hypertension in patients with
cirrhosis. Aliment Pharmacol Ther. 2016;43:1222–31.
21. Leeming D, Veidal S, Karsdal M, et al. Pro-C5,
a marker of true type V collagen formation and
fibrillation, correlates with portal hypertension in
patients with alcoholic cirrhosis. Scand J Gastroenterol.
2015;50(5):584–92.
22. Hametner S, Ferlitsch A, Ferlitsch M, et al. The VITRO
score (Von Willebrand factor antigen/thrombocyte
ratio) as a new marker for clinically significant portal
hypertension in comparison to other non-invasive
parameters of fibrosis including ELF test. PLoS One.
344
Acta Med Indones-Indones J Intern Med
2016;11(2):e0149230.
23. Bruha R, Jachymova M, Petrtyl J, et al. Osteopontin:
A non-invasive parameter of portal hypertension and
prognostic marker of cirrhosis. World J Gastroenterol.
2016;22(12):3441–50.
24. Lim Y, Choi E, Jang Y, et al. Clinical implications of the
serum apelin level on portal hypertension and prognosis
of liver cirrhosis. Gut Liver. 2016;10(1):109–16.
25. Kirnake V, Arora A, Sharma P, et al. Non-invasive
aspartate aminotransferase to platelet ratio index
correlates well with invasive hepatic venous pressure
gradient in cirrhosis. Indian J Gastroenterol. 2018;
37(4):335-341.
26. Zou Z, Yan X, Li C, et al. von Willebrand factor as a
biomarker of clinically significant portal hypertension
and severe portal hypertension: a systematic review and
meta-analysis. BMJ Open. 2019;9:e025656.
27. Yen Y, Kuo F, Kee K, et al. APRI and FIB-4 in the
evaluation of liver fibrosis in chronic hepatitis C
patients stratified by AST level. PLoS One. 2018;1–16.
28. Cho EJ, Kim MY, Lee JH, et al. Diagnostic and
prognostic values of noninvasive predictors of portal
hypertension in patients with alcoholic cirrhosis. PLoS
ONE. 2015;10(7):e0133935. DOI: 10.1371/journal.
pone. 0133935.
29. Leung JC, Loong TC, Pang J, et al. Invasive and non-
invasive assessment of portal hypertension. Hepatol
Int. 2017;30–2.
30. Ferraioli G, Wong V, Castera L, et al. Liver ultrasound
elastography: An update to the World Federation
for ultrasound in medicine and biology guidelines
and recommendations. Ultrasound Med Biol.
2018;44(12):2419–40.
31. Owen C, Meyers P. Sonographic evaluation of the
portal and hepatic systems. Journal of Diagnostic
Medical Sonography. 2006;22(5):317-328. DOI:
10.1177/8756479306293101.
32. Kondo T, Maruyama H, Sekimoto T, et al.
Impact of portal hemodynamics on Doppler
ultrasonography for predicting decompensation
and long-term outcomes in patients with cirrhosis.
Scand J Gastroenterol. 2016;51(2):236-244. DOI:
10.3109/00365521.2015.1081275.
33. Kim MY, Baik SK, Park DH, et al. Damping index of
Doppler hepatic vein waveform to assess the severity
of portal hypertension and response to propranolol
in liver cirrhosis: A prospective nonrandomized
study. Liver International. 2007;27(8):1103-10. DOI:
10.1111/j.1478-3231.2007.01526.x.
34. Vizzutti F, Arena U, Rega L, et al. Performance of
Doppler ultrasound in the prediction of severe portal
hypertension in hepatitis C virus-related chronic liver
disease. Liver International. 2007; 27(10): 1379-1388.
DOI: 10.1111/j.1478-3231.2007.01563.x.
35. Franchis R De, Vi B. Position paper expanding
consensus in portal hypertension Report of the
Baveno VI Consensus Workshop: Stratifying risk and
Vol 54 • Number 2 • April 2022 National Consensus on Portal Hypertension Management in Indonesia
individualizing care for portal hypertension. J
Hepatol. 2015;63(3):743–52.
36. Colecchia A, Montrone L, Scaioli E, et al. Measurement
of spleen stiffness to evaluate portal hypertension
and the presence of esophageal varices in patients
with HCV-related cirrhosis. Gastroenterology.
2012;143(3):646–54.
37. Sharma BC, Sarin SK. Hepatic venous pressure
gradient in cirrhosis: Role in variceal bleeding,
non-bleeding complications and outcome. Asian
Journal of Surgery. 2006; 29(3): 113-119.
38. Choi SY, Jeong WK, Kim Y, et al. Shear-wave
elastography: A noninvasive tool for monitoring
changing hepatic venous pressure gradients in
patients with cirrhosis. Radiology. 2014;273(3):
917-26.
39. Thalheimer U, Mela M, Patch D, et al. Monitoring
target reduction in hepatic venous pressure
gradient during pharmacological therapy of
portal hypertension: A close look at the evidence.
Gut. 2004;53(1):143–8.
40. Nicoară-farcău O, Stefănescu H, Tanțău M, et
al. Diagnostic challenges in non-cirrhotic portal
hypertension - porto sinusoidal vascular disease.
World J Gastroenterol. 2020;26(22):3000–11.
41. Runyon B. Introduction to the revised American
Association for the Study of Liver Diseases Practice
Guideline management of adult patients with ascites
due to cirrhosis 2012. Hepatology. 2013;57(4):1651–3.
42. Huelin P, Fortea JI, Crespo J, et al. Ascites: treatment,
complications, and prognosis. In: Rodrigo L, editor.
Ascites - physiopathology, treatment, complications
and prognosis. Intech Open; 2017.
43. Pockros P, Reynolds T. Rapid diuresis in patients with
ascites from chronic liver disease: the importance of
peripheral edema. Gastroenterology. 1986;90:1827–33.
44. Casado M, Bosch J, Garcia-Pagan J, et al. Clinical
events after transjugular intrahepatic portosystemic
shunt: correlation with hemodynamic findings.
Gastroenterology. 1998;114:1296–303.
45. Riggio O, Angeloni S, Salvatori F, et al. Incidence, natural
history, and risk factors of hepatic encephalopathy after
transjugular intrahepatic portosystemic shunt with
polyetrafluoroethylene-covered stent grafts. Am J
Gastroenterol. 2008;103:2738–46.
46. Sauerbruch T, Mengel M, Dollinger M, et al.
Prevention of rebleeding from esophageal varices in
patients with cirrhosis receiving small-diameter stents
vs hemodynamically controlled medical therapy.
Gastroenterology. 2015;149:660–8.
47. Caldwell J, Edriss H, Nugent K. Chronic peritoneal
indwelling catheters for the management of malignant
and nonmalignant ascites. Proc (Bayl Univ Med Cent).
2018;31(3):297–302.
48. Reinglas J, Amjadi K, Petrcich BP, et al. The palliative
management of refractory cirrhotic ascites using the
PleurX (©) catheter. Can J Gastroenterol Hepatol.
2016;4680543.
49. Rossle M, Gerbes AL. TIPS for the treatment of
refractory ascites, hepatorenal syndrome and hepatic
hydrothorax: a critical update. Gut. 2010;59:988–1000.
50. Kashani A, Landaverde C, Medici V, et al. Fluid
retention in cirrhosis: pathophysiology and
management. Q J Med. 2008;101:71–85.
51. Garbuzenko D, Arefyev N. Hepatic hydrothorax: an
update and review of the literature. World J Hepatol.
2017;1197–204.
52. Badillo R, Rockey D. Hepatic hydrothorax: clinical
features, management, and outcomes in 77 patients
and review of the literature. Medicine (Baltimore).
2014;93:135–42.
53. Hou F, Qi X, Guo X. Effectiveness and safety of
pleurodesis for hepatic hydrothorax: A systematic
review and meta-analysis. Dig Dis Sci. 2016;61:3321–
34.
54. Huang P, Kuo S, Chen J, et al. Thoracoscopic mesh
repair of diaphragmatic defects in hepatic hydrothorax:
results of a survey. Ann Thorac Surg. 2016;101:1921–7.
55. Attar B. Approach to hyponatremia in cirrhosis. Clin
Liver Dis. 2019;13:98–101.
56. Kim W, Biggins S, Kremers W, et al. Hyponatremia
and mortality among patients on the liver-transplant
waiting list. N Engl J Med. 2008;359:1018–26.
57. Cárdenas A, Ginès P, Marotta P, et al. Tolvaptan,
an oral vasopressin antagonist, in the treatment of
hyponatremia in cirrhosis. J Hepatol. 2012;56:571–8.
58. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan
in patients with autosomal dominant polycystic kidney
disease. N Engl J Med. 2012;367:2407–18.
59. Evans L, Kim W, Poterucha J, et al. Spontaneous
bacterial peritonitis in asymptomatic outpatients with
cirrhotic ascites. Hepatology. 2003;37:897–901.
60. Feldman M, Friedman L, Brandt J. Sleisenger and
Fordtran’s gastrointestinal and liver disease. 8th ed.
Saunders. Philadelphia; 2006. p. 1935–64.
61. Rimola A, Salmeron J, Clemente G, et al. Two
different dosages of cefotaxime in the treatment of
spontaneous bacterial peritonitis in cirrhosis: results
of a prospective, randomized, multicenter study.
Hepatology. 1995;21:674–9.
62. Ricart E, Soriano G, Novella M, et al. Amoxicillin-
clavulanic acid vs cefotaxime in the therapy of
bacterial infections in cirrhotic patients. J Hepatol.
2000;32:596–602.
63. DeLemos A, Ghabril M, Rockey D, et al. Drug-induced
liver injury network (DILIN). Amoxicillin-clavulanate-
induced liver injury. Dig Dis Sci. 2016;61:2406–16.
64. Fernandez J, Acevedo J, Castro M, et al. Prevalence
and risk factors of infections by multiresistant
bacteria in cirrhosis: a prospective study. Hepatology.
2012;55:1551–61.
65. Magiorakos A, Srinivasan A, Carey R, et al. Multidrug-
resistant, extensively drug-resistant and pandrug-
resistant bacteria: an international expert proposal for
345
Juferdy Kurniawan
interim standard definitions for acquired resistance.
Clin Microbiol Infect. 2012;18:268–81.
66. Fernández J, Ruiz L, Arbol DEL, et al. Norfloxacin
vs Ceftriaxone in the prophylaxis of infections in
patients with advanced cirrhosis and hemorrhage.
Gastroenterology. 2006;131(4):1049–56.
67. Singh N, Gayowski T, Yu V, et al. Trimethoprim-
sulfamethoxazole for the prevention of spontaneous
bacterial peritonitis in cirrhosis: a randomized trial.
Ann Intern Med. 1995;122(8):595–8.
68. G a r c i a - Ts a o G . B a c t e r i a l i n f e c t i o n s i n
cirrhosis: treatment and prophylaxis. J Hepatol.
2005;42(Supple(1)):S85-92.
69. Angeli P, Ginès P, Wong F, et al. Diagnosis and
management of acute kidney injury in patients with
cirrhosis: Revised consensus recommendations
of the International Club of Ascites. J Hepatol.
2015;62(4):968–74.
70. Allegretti AS, Sola E, Gines P. Clinical application of
kidney biomarkers in cirrhosis. Am J Kidney Dis. 2020;
76(5): 710-719. DOI: 10.1053/j.ajkd.2020.03.016.
71. Wong F, Nadim MK, Kellum JA, et al. Working
party proposal for a revised classification system
of renal dysfunction in patients with cirrhosis. Gut.
2011;60(5):702–9.
72. Erly B, Carey WD, Kapoor B, et al. Hepatorenal
syndrome: A review of pathophysiology and current
treatment options. Semin Intervent Radiol. 2015; 32(4):
445-454. DOI: 10.1055/s-0035-1564794.
73. Biggins SW, Angeli P, Garcia-Tsao G, et al. Diagnosis,
evaluation, and management of ascites and hepatorenal
syndrome. Hepatology. 2021. DOI: 10.1002/hep.31884.
74. Esrailian E, Pantangco ER, Kyulo NL, et al. Octreotide/
midodrine therapy significantly improves renal
function and 30-day survival in patients with type 1
hepatorenal syndrome. Dig Dis Sci. 2007;52(3):742–8.
75. Guevara M, Ginès P, Bandi JC, et al. Transjugular
intrahepatic portosystemic shunt in hepatorenal
syndrome: Effects on renal function and vasoactive
systems. Hepatology. 1998;28(2):416–22.
76. Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in
cirrhosis: Evidence-based indications and limitations.
JHEP Reports. 2020;2(1):100063.
77. Sarin SK, Kumar A, Angus PW, et al. Diagnosis and
management of acute variceal bleeding: Asian Pacific
Association for study of the liver recommendations.
Hepatol Int. 2011;5(2):607–24.
78. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention
and management of gastroesophageal varices and
variceal hemorrhage in cirrhosis. Hepatology.
2007;46(3):922–38.
346
Acta Med Indones-Indones J Intern Med
79. Salcedo M, Alonso S, Rincón D, et al. Endoscopic
treatment versus endoscopic plus pharmacologic
treatment for acute variceal bleeding: A meta-analysis.
Hepatology. 2002;35(3):609–15.
80. Ríos Castellanos E, Seron P, Gisbert JP, et al.
Endoscopic injection of cyanoacrylate glue versus
other endoscopic procedures for acute bleeding gastric
varices in people with portal hypertension. Cochrane
Database Syst Rev. 2015;2015(5).
81. Villanueva C, Escorsell À. Optimizing general
management of acute variceal bleeding in cirrhosis.
Curr Hepat Rep. 2014;13(3):198–207.
82. Escorsell À, Pavel O, Cárdenas A, et al. Esophageal
balloon tamponade versus esophageal stent in
controlling acute refractory variceal bleeding: A
multicenter randomized, controlled trial. Hepatology.
2016;63(6):1957–67.
83. Amarapurkar PD, Amarapurkar DN. Management of
coagulopathy in patients with decompensated liver
cirrhosis. Int J Hepatol. 2011;2011:1–5.
84. Yoshikawa I, Murata I, Nakano S, et al. Effects of
endoscopic variceal ligation on portal hypertensive
gastropathy and gastric mucosal blood flow. Am J
Gastroenterol. 1998;93(1):71–4.
85. Nakamura K, Honda K, Akahoshi K, et al. Suitability of
the expanded indication criteria for the treatment of early
gastric cancer by endoscopic submucosal dissection:
Japanese multicenter large-scale retrospective
analysis of short- and long-term outcomes. Scand J
Gastroenterol. 2015;50(4):413–22.
86. Nguyen H, Le C, Ngyuyen H. Gastric antral vascular
ectasia (watermelon stomach) – An enigmatic and
often overlooked cause of gastrointestinal bleeding in
the elderly. The Permanente Journal. 2009;13(4):46-9.
87. Kamath PS, Lacerda M, Ahlquist DA, et al. Gastric
mucosal responses to intrahepatic portosystemic
shunting in patients with cirrhosis. Gastroenterology.
2000;118(5):905–11.
88. Zenker M. Argon plasma coagulation. GMS
Krankenhaushygiene Interdisziplinar. 2008;3(1).
89. Hanafy A, El Hawary A. Efficacy of argon plasma
coagulation in the management of portal hypertensive
gastropathy. Endosc Int Open. 2016;04(10):E1057–62.
90. Gjeorgjievski M, Cappell MS. Portal hypertensive
gastropathy: A systematic review of the
pathophysiology, clinical presentation, natural history,
and therapy. World J Hepatol. 2016;8(4):231-262. DOI:
10.4254/wjh.v8.i4.231.